tbuckley/cabot-search huggingface dataset:
DDDR-31. TARGETING CANCER STEM CELLS WITH A CDK2 INHIBITOR IN GLIOBLASTOMA
Authors: Elham Mahmoudian, Dianbo Qu, Arezu Jahani-Asl
Journal: Neuro-Oncology (2023)

Abstract Glioblastoma (GB) is the most common and aggressive adult brain tumor with no cure. Brain tumor stem cells (BTSCs) are a rare population of self-renewing multipotent stem cells in GB that contribute to tumorigenesis, therapeutic resistance and tumour recurrence. Here, we report a CDK2 inhibitor that suppresses BTSCs via OSM/OSMR/STAT3 signalling pathway. To begin with we performed high throughput screening (HTS) of ~8400 compounds including FDA-approved drugs in patient derived human BTSCs that naturally harbour EGFRvIII mutation and elevated STAT3 phosphorylation, in search of compounds that can suppress EGFRvIII/OSMR/STAT3 oncogenic pathway. The screen led to the identification of a panel of CDK inhibitors that possessed important characteristics including a) ability to cross the blood-brain barrier with mall molecular weights of 277-566 kDa, b) low Topological Polar Surface Area (TPSA) of 76-115 A°, c) a low number of Hydrogen Bond Donors (HBDs) (1-4), and d) cLogP values ranging from 2-4. Following counter screens, we focused on a CDK2 inhibitor that significantly and most efficiently reduced OSM/OSMR signalling and STAT3 activation. Importantly, we found that the compound inhibited the self-renewal and growth of BTSCs in EGFRvIII subtype of BTSCs. This research has led to future investigation on in vivo assessment of this CDK2 inhibitor in combination with ionizing radiation and chemotherapy in preclinical models of GB.
DDDR-17. CLINICAL RESPONSE TO THE PDGFRA/KIT INHIBITOR AVAPRITINIB IN PEDIATRIC AND YOUNG ADULT HIGH-GRADE GLIOMA PATIENTS
Authors: Lisa Mayr, Maria Trissal, Kallen Schwark, Sina Neyazi, Alexander Beck, Jenna Labelle, Joana Graca Marques, Liesa Weiler-Wichtl, Sibylle Madlener, Seongbae Kong, Madeline Miclea, Jeffrey Supko, Armin Sebastian Guntner, Hana Palova, Jakub Neradil, Natalia Stepien, Daniela Loetsch-Gojo, Christian Dorfer, Karen Dieckmann, Andreas Peyrl, Amedeo A Azizi, Alicia-Christina Baumgartner, Ondrej Slaby, Petra Pokorna, Frank Dubois, Noah Greenwald, Pratiti Bandopadhayay, Rameen Beroukhim, Keith Ligon, Christof Kramm, Annika Bronsema, Simon Bailey, Ana Guerreiro Stuecklin, Sabine Mueller, Mary Skrypek, Nina Martinez, Daniel C Bowers, David Jones, Chris Jones, Natalie Jaeger, Jaroslav Sterba, Leonhard Müllauer, Christine Haberler, Chandan Kumar-Sinha, Arul Chinnaiyan, Rajen Mody, Julia Furtner-Srajer, Carl Koschmann, Johannes Gojo, Mariella Filbin
Journal: Neuro-Oncology (2023)

Abstract PDGFRA has been shown to be commonly altered in pediatric and young adult high-grade gliomas (pHGGs) including histone 3 lysine 27-mutated diffuse midline gliomas (H3K27M DMG), a disease with almost no long-term survivors. Here, we performed comprehensive genomic and transcriptomic analyses of n=259 pediatric high-grade glioma cases which revealed PDGFRA genomic alterations (mutations and/or amplifications) in ~14.9% of patients. We tested a panel of patient-derived HGG and H3K27M DMG models against a range of PDGFRA inhibitors, and found that avapritinib outperformed other inhibitors in terms of (1) in vitro efficacy, (2) selectivity for PDGFRA inhibition and (3) blood brain barrier penetration, and demonstrated significant survival impact and PDGFRA pathway inhibition in two orthotopic H3K27M DMG mouse models. We furthermore report the first clinical experience using avapritinib in eight pediatric and young adult patients with high-grade glioma (H3K27M DMG and/or PDGFRA altered). Avapritinib was generally well tolerated with a manageable safety profile and no significant safety concerns. Preliminary data reveal radiographic response evaluated by RAPNO criteria in 3/7 (42%) patients with evaluable lesions. Complete or partial response was observed in 2 of 8 patients (25%); one patient showed stable disease; 5 of 8 patients progressed on therapy (62%). Molecular profiling of treated patients revealed PDGFRA amplification in 4 of 8 patients, PDGFRA receptor mutations in 4 of 8 patients. One patient with PDGFRA/KIT amplification developed a spontaneous EGFR gain and a secondary PDGFRA mutation in a cerebellar metastatic lesion that progressed on avapritinib therapy. In summary, we report that avapritinib, a selective, CNS penetrant small molecule inhibitor of PDGFRA has potent activity in preclinical models and produced clinical responses with good tolerability in pediatric and young adult patients with high-grade glioma, suggesting a promising role for avapritinib therapy in HGG patients.
CTNI-51. A RANDOMIZED DOUBLE-BLIND PHASE 3 STUDY OF VORASIDENIB VS PLACEBO IN PATIENTS WITH MUTANT <i>IDH1</i>/<i>2</i> DIFFUSE GLIOMA (INDIGO): EXPLORATORY ANALYSIS OF VARIANT ALLELE FREQUENCY AND PROGRESSION-FREE SURVIVAL
Authors: Timothy Cloughesy, Ingo Mellinghoff, Martin van den Bent, Deborah Blumenthal, Mehdi Touat, Katherine Peters, Jennifer Clarke, Joe Mendez, Shlomit Yust-Katz, Warren Mason, Francois Ducray, Yoshie Umemura, L Burt Nabors, Matthias Holdhoff, Andreas Hottinger, Yoshiki Arakawa, Juan Sepúlveda, Wolfgang Wick, Riccardo Soffietti, James Perry, Pierre Giglio, Macarena de la Fuente, Elizabeth Maher, Sung Choe, Dan Zhao, Shuchi Pandya, Lori Steelman, Islam Hassan, Adriana Tron, Patrick Wen
Journal: Neuro-Oncology (2023)

Abstract INTRODUCTION Vorasidenib is an oral, brain-penetrant, inhibitor of mutant isocitrate dehydrogenase (mIDH) 1/2 enzymes. The INDIGO study (NCT04164901) showed significantly improved radiographic progression-free survival (PFS) by blinded independent review committee (BIRC) with vorasidenib, compared with placebo, in patients with mIDH1/2 adulttype diffuse glioma (hazard ratio [HR] 0.39, 95% CI 0.27–0.56; one-sided P = 0.000000067 [Mellinghoff N Engl J Med 2023]). The key secondary endpoint of time-to-next-intervention was also met. METHODS In this double-blind Phase 3 study, patients aged ≥ 12 years with residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma, measurable non-enhancing disease, and no prior treatment for glioma were randomized 1:1 to receive vorasidenib 40 mg or placebo daily in 28-day cycles. An investigational clinical trial assay centrally confirmed IDH1 R132H/C/G/S/L or IDH2 R172K/M/W/S/G mutation variants. Pretreatment (archival) tumor tissue was analyzed by next-generation sequencing for CDKN2A/B homozygous deletion and other co-mutations (ACE Extended Cancer Panel). RESULTS As of Sep 6, 2022 (preplanned second interim analysis), 168 patients were randomized to vorasidenib and 163 to placebo (median age, 40.0 years; Karnofsky performance scale = 100, 53.5%; oligodendroglioma, 172; astrocytoma, 159; mIDH1, 315; mIDH2, 16). Two patient subgroups were defined by baseline IDH1/2 variant allele frequency (VAF): lower/higher than the median value (0.377). The median PFS results favored vorasidenib over placebo in both subgroups (low VAF, one-sided P = 0.0116; high VAF, one-sided P &amp;lt; 0.0001). Vorasidenib and placebo groups had similar and a low number of co-mutations in known/likely oncogenic genes at baseline (median number of co-mutations across both groups was 4). CDKN2A homozygous deletion was detected in only two participants (both in the placebo group). Additional data will be presented. CONCLUSION In the first randomized Phase 3 study of a targeted therapy in grade 2 mIDH1/2 glioma, vorasidenib prolonged median PFS by BIRC, relative to placebo, irrespective of IDH1/2 VAF.
CCRG-05. A UNIFYING AND SELF-REINFORCING MECHANISM OF TUMOR IMMORTALITY IN <i>TERT</i> PROMOTER MUTANT CANCERS
Authors: Nicholas Stevers, Carter Barger, Jimmy Yuan, Somang Kim, Chibo Hong, Olivia Lenzo, Andrew McKinney, Samuel Wu, Yu-Jin Lee, Sara Collins, Georgios Batsios, Darwin Kwok, Abigail Suwala, Christina Appin, Pavithra Viswanath, Noriyuki Kasahara, John Gordan, Annette Molinaro, Jun Song, Joseph Costello
Journal: Neuro-Oncology (2023)

Abstract Telomerase Reverse Transcriptase promoter mutations enable tumor cell immortality in millions of cancer patients annually. While prior therapies targeting telomerase lacked tumor selectivity and were poorly tolerated, TERT promoter mutations and their regulation present a unique opportunity for tumor specific reversal of cellular immortality. The two hotspot mutations, G228A and G250A, generate identical de novo E26 transformation specific (ETS) transcription factor binding sites. However, the 28 ETS factors share a similar binding site preference, raising the question of whether all ETS factors can reactivate TERT. In glioblastoma and a few other cancers, we have shown the de novo ETS site along with a nearby native ETS site (ETS-195/200) recruit one ETS factor, the GA-binding protein (GABP) tetramer, to reactivate TERT. This GABP-mediated mechanism may be restricted to specific cancer types and the two hotspot mutations or could be widely relevant to any cancer with a de novo ETS TERT promoter mutation. We have found that the GABP tetramer activates 6 distinct mutant TERT promoters across 16 different cancer types. However, TERT expression is maintained in most tetramer depleted tumor cells as the tetramer is serially replaced by GABP dimers and weakly by a paralogous tetramer complex that increase following disengagement of GABP tetramer-mediated negative feedback loops. Elimination of both the tetramer and dimer reinstates epigenetic repression of TERT, shortens telomeres, and prevents cancer cell division. However, some knockout cancer cells avoid this fate through weak activation of TERT by the paralogous GABP tetramer complex. The compensatory maintenance of TERT expression can be overcome with a dominant negative GABPB1, leading to TERT silencing, evidenced by gene expression and non-invasive metabolic imaging correlates, and telomere shortening in TERT promoter mutant glioblastoma. We are currently investigating the delivery of this dominant negative to tumor cells via clinically approved retroviral replicating vectors.
CNSC-20. MGMT PROMOTER METHYLATED HIGH GRADE GLIOMA WITH DISTANT RECURRENCE AND STABLE ORIGINAL TUMOR SITE: CASE SERIES
Authors: Ronak Jani, Jonathan Lee, Ignacio Jusue-Torres, Anand Germanwala, Ewa Borys, Abhishek Solanki, Atul Mallik, Kevin Barton, Vikram Prabhu
Journal: Neuro-Oncology (2023)

Abstract Recurrence pattern in high grade glioma is classified as local and distant recurrence based on distance from original resection cavity and radiation field. We report the first series of three cases of O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated high grade glioma with distant recurrence without local recurrence throughout the disease course. Patient 1: 65 year-old female with WHO grade 4 glioblastoma, isocitrate dehydrogenase enzyme (IDH) wild type (WT), MGMT methylated. She underwent gross total resection followed by Stupp protocol. Postoperative ischemic volume was &amp;lt; 1 ml. Distant recurrence occurred 4 months after completion of Stupp protocol. Patient 2: 55 year-old male with WHO grade 4 glioblastoma, IDH wild type, MGMT methylated. He underwent gross total resection followed by Stupp protocol. Postoperative ischemic volume was 18 ml. Distant recurrence occurred 5 months after completion of Stupp protocol. Patient 3: 31 year-old male with WHO grade 4 astrocytoma, IDH mutant, MGMT promoter methylated. He underwent gross total resection followed by Stupp protocol. Postoperative ischemic volume was 2 ml. Distant recurrence occurred 10 months after completion of Stupp protocol. Distant recurrence is more common in MGMT promoter methylated tumors. All 3 patients in our case series had poor outcomes after distant recurrence without local recurrence at the original tumor site. This observation indicates good local control in MGMT promoter methylated high grade glioma with current standard treatment. For one patient, next generation sequencing (NGS) was available for both original and recurrent tumor and did not reveal any major differences in the genetics of original tumor and distant recurrent tumor other than temozolomide induced high tumor mutational burden in the distant recurrent tumor. Understanding risk factors for distant recurrence in MGMT promoter methylated high grade gliomas and investigating correlations between recurrences will help plan therapeutic strategies to prevent distant recurrence and improve outcomes.
CSIG-33. A 2ND GENERATION IDO1 PROTEIN DEGRADER TO OVERCOME NON-ENZYME-MEDIATED IDO1-DEPENDENT IMMUNE SUPPRESSION FOR GLIOBLASTOMA
Authors: Prashant Bommi, Paige Monsen, Kristen Lauing, Lijie Zhai, Kevin Barton, Ewa Borys, Douglas Anderson, Vikram Prabhu, Jigisha Thakkar, Rimas Lukas, Gary Schiltz, Derek Wainwright
Journal: Neuro-Oncology (2023)

Abstract Indoleamine 2,3-dioxygenase 1 (IDO1) is an immunosuppressive rate-limiting enzyme that metabolizes the essential amino acid, tryptophan (Trp), into the downstream catabolite, kynurenine. IDO1 is expressed in &amp;gt;90% of patient-resected glioblastoma (GBM). We recently validated that IDO1 can suppress the anti-brain tumor immune response and ablate immunotherapeutic treatment efficacy through non-metabolic IDO1 activity. To-date, most IDO1-targeted therapy has focused on inhibiting tryptophan metabolism. This class of drugs has failed to improve the overall survival of patients with cancer. To overcome this failure, we developed a therapeutic agent that inhibits both IDO1 enzyme- and non-enzyme-activities in the form of an IDO1-Proteolysis Targeting Chimera (PROTAC). We previously published the characterization of a 1st generation lead compound (Bollu et al., 2022; J. Med. Chem) with a DC50 for IDO1 of 0.329 µM in human GBM cells. In a more recent investigation, we discovered a 2nd generation IDO1-PROTAC, NU227326, with 30× more potency and a DC50 of 10.4 nM in human GBM cells. IDO1-expressing U87, U138, and patient derived xenograft (PDX) GBM43 were treated with either IDO1-PROTAC, IDO1-mutant-PROTAC, IDO1 enzyme inhibitor, or IDO1 siRNA. Transcriptomic analysis revealed differentially expressed genes that were commonly regulated after treatment with the IDO1-PROTAC as compared to treatment with the IDO1-mutant-PROTAC or IDO1 enzyme inhibitor groups in U87, U138, and GBM43 cells. Mass spectrometry discovered 34 unique proteins that were differentially expressed inside of human GBM cells and an additional 20 unique proteins that were identified in the supernatant of cultured human GBM cells after IDO1-PROTAC treatment. Meta-analysis of the transcriptomic and proteomic analyses identified a novel factor that was unique to IDO1-PROTAC treatment. IDO1-PROTAC treatment-enriched GO terms were associated with nucleoside kinase and metallocarboxypeptidase activities. This study discovered multiple new pathways that immunosuppressive IDO1 non-metabolically regulates in human glioblastoma cells.
BIOM-03. LACK OF CORRELATION OF MR-DETERMINED WHITE MATTER INJURY(WMI)WITH NEUROCOGNITIVE FUNCTION (NCF)6 MONTHS FOLLOWING WBRT+/-HIPPOCAMPAL AVOIDANCE(HA)+MEMANTINE:SECONDARY ANALYSIS OF NRG ONCOLOGY NRGCC001
Authors: Joseph Bovi, Stephanie Pugh, Paul Brown, Vinai Gondi, Clifford Robinson, Jeffrey Wefel, David Sabsevitz, Markus Sprenger, Vijayananda Kundapur, David Roberge, Kiran Devisetty, Sunjay Shah, Kenneth Usuki, Baldassarre Stea, Harold Yoon, Eric Donnelly, Nadia Laack, Andrew Baschnagel, Rebecca Paulus, Lisa Kachnic
Journal: Neuro-Oncology (2023)

Abstract PURPOSE Previous analysis of NRG-CC001 suggested pre-treatment WMI volume was a significant imaging-biomarker predictor of post-treatment neurocognitive decline at 4-and 12-months following HA-WBRT+Memantine. This suggested patients with greater pre-treatment WMI were more susceptible to neurocognitive decline, specifically when undergoing HA-WBRT, but not standard-WBRT. The current analysis examined the relationship between changes in MR-determined WMI and NCF 6-months following WBRT+memantine+/-HA. METHODS NCF-testing was performed at baseline, 2, 4, 6, and 12 months post-WBRT, and included Hopkins Verbal Learning Test–Revised (HVLT-R), Trail Making Test (TMT) Parts A and B, and Controlled Oral Word Association (COWA). Pre-treatment WMI was measured by FLAIR-volume corrected for whole brain volume and corrected for the FLAIR volume associated with metastases (met vol) (FLAIR-volume/(whole brain volume–met-vol). Pearson correlation coefficients were used to assess the correlation between pre-treatment WMI and change from baseline to 6-months for each standardized NCF score. RESULTS Of the 518 randomized patients, 443 (217 patients WBRT+Memantine and 226 HA-WBRT+Memantine) had WMI data available at baseline, and of those, 162 patients (89 patients WBRT+Memantine and 73 HA-WBRT+Memantine) had both baseline and 6-month imaging available. For these patients, there was only a trend toward significance for change in corrected FLAIR-volume from baseline to 6-months (p = 0.174) but no significant change in met-vol (p = 0.438) or whole brain volume (p = 0.977). The change in standardized TMT Part A and B and the change in composite 6-month change scores were moderately correlated with change in corrected FLAIR volume adjusted for met-vol but only in the WBRT+Memantine arm (rho=-0.35, -0.34, -0.39 and p-value = 0.003, 0.006, 0.001). CONCLUSIONS Despite an increase in post-WBRT MR-WMI at 6-months, analysis did not show strong correlation between NCF and MR-WMI as determined by FLAIR-volume change between baseline and 6-months. Similar analyses are underway for the NRG-CC003 imaging data.
EXTH-06. GLIOBLASTOMA PATIENT SPECIFIC TRANSCRIPTOME REMODELING IN RESPONSE TO MDM2 ANTAGONIST TREATMENT OF WILD-TYPE P53 CANCER STEM CELLS IS ASSOCIATED WITH SENSITIVITY AND STRATEGIES FOR COMBINATION THERAPY
Authors: Yuling Meng, Nouman Mughal, Indrani Datta, Oluwademilade Nuga, Susan Irtenkauf, Laura Hasselbach, Kristyn Quenneville, Stephen Brown, Ana deCarvalho
Journal: Neuro-Oncology (2023)

Abstract Over 70% of glioblastomas are p53 wild-type and these patients could benefit from p53 reactivation treatment. Here we determined the sensitivity of a glioblastoma patient-derived cancer stem cells (CSCs) panel to three MDM2 antagonists (MDM2a) to test to what extent transcriptional reprogramming is affected by genomic background and correlates to response to acute treatment with MDM2 antagonists. IC50 concentrations and area above the curve (AAC) were measured from dose response curves obtained from 4 and 7-day treatment. The inhibitors were specific to wt-p53 CSCs, but these presented a wide range of sensitivity. Seven wt-p53 CSCs were treated RG7112 IC50 concentrations or DMSO control for 24h (n=4). RNA was isolated for Illumina Truseq stranded mRNA libraries sequenced at 30M depth. Quantified raw counts were processed using NOISeq R package to determine differentially expressed genes (DEG) between control and treated samples. In addition to the expected high representation of upregulated p53 targets in all cell lines, we observed significan cell specific transcriptome alterations, including enrichment of survival pathways, such as mTOR, ERK and NFkB in the less sensitive CSC lines, which did not readily correlate with the individual genomic landscapes. E2F targets, G2-M cell cycle check point and DNA-repair pathways were highly enriched in the downregulated genes. Combination of MDM2a with radiation treatment (RT) was synergistic to a subset of CSCs. As validation we found that MDM2a treatment was effective in sensitizing a resistant orthotopic mouse glioblastoma PDX to fractionated RT, with maximum efficacy when treatment started 24h prior to RT vs simultaneously (Log-rank Mantel-Cox test: p=0.0006 vs 0.0277). The integration of the treatment-mediated transcriptional patterns with differential sensibility to MDM2 antagonists and genomic landscape of the CSC panel provides a platform to identify targets for combination therapies, which is the most promising clinical application of the reactivation of wt-p53 in GBMs.
BIOS-06. MACHINE LEARNING MADE EASY: DESIGN OF A PROPOSAL FOR A MEDICAL STUDENT EDUCATIONAL SESSION ON HIGH YIELD STRATEGIES FOR LEARNING AND APPLYING DATA SCIENCE
Authors: Nolan Brown, Cathleen Kuo, Zachery Neil, Julian Gendreau
Journal: Neuro-Oncology (2023)

Abstract Machine learning is a burgeoning field in data science that has many applications in medicine, and it is especially useful in neurosurgery due to the often-complex and potentially emergent nature of day-to-day cases. Machine learning models have the potential to deliver accurate patient prognostication while offering the benefit of providing real-time AI supported clinical decision-making with high data granularity. These models can utilize numerical inputs for more straightforward applications and, with practice, can enable clinicians and trainees to incorporate advanced imaging sequences as inputs to optimize the accuracy of patient prognostication. In the future, these models will become much more commonplace in the clinical setting for neurosurgeons. As medical school curricula do not typically incorporate these statistical techniques into biomedical statistics courses, symposia centered on machine learning could prove essential to medical students seeking to learn these skills. This session would include a brief overview of machine learning models and the procedures for using the programming language of RStudio for the development of novel internet-based prognostication calculators. The benefit of RStudio is that it is user friendly and pre-designed templates are available that can enable students to perform facile customization in tailoring the code to the needs of their clinical investigation. There will be a brief overview of accuracy verification involving discussion of receiver operating curves with the use of training and testing datasets - the heart of machine learning. We have designed and outlined a curriculum that will enable students to identify and classify different techniques (support vector machines, logistic regression, clustering, nearest neighbor classifiers), and recognize the utility of machine learning approaches to neurosurgical outcomes prognostication. Our hope is that students will leave this symposium well-equipped with a newfound confidence and the baseline conceptual framework needed to begin exploring the awesome world of machine learning throughout their training.